The p53 mRNA-Mdm2 Interaction Controls Mdm2 Nuclear Trafficking and Is Required for p53 Activation following DNA Damage

• Published in: Cancer cell Vol. 21; no. 1; pp. 25 - 35
• Main Authors: Gajjar, Madhavsai, Candeias, Marco M., Malbert-Colas, Laurence, Mazars, Anne, Fujita, Jun, Olivares-Illana, Vanesa, Fåhraeus, Robin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2012
• Subjects: Active Transport, Cell Nucleus; Cell Line, Tumor; DNA Damage; Gene Expression Regulation; Humans; Phosphorylation; Proto-Oncogene Proteins c-mdm2 - metabolism; RNA, Messenger - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2011.11.016

The ATM kinase and p53 are key tumor suppressor factors that control the genotoxic stress response pathway. The ATM substrate Mdm2 controls p53 activity by either targeting p53 for degradation or promoting its synthesis by binding the p53 mRNA. The physiological role and regulation of Mdm2's dual function toward p53 is not known. Here we show that ATM-dependent phosphorylation of Mdm2 at Ser395 is required for the p53 mRNA-Mdm2 interaction. This event also promotes SUMO-conjugation of Mdm2 and its nucleoli accumulation. Interfering with the p53 mRNA-Mdm2 interaction prevents p53 stabilization and activation following DNA damage. These results demonstrate how ATM activity switches Mdm2 from a negative to a positive regulator of p53 via the p53 mRNA. ► p53 stabilization following genotoxic stress requires the p53 mRNA-Mdm2 interaction ► Mdm2 acts as a positive regulator of p53 activity following DNA damage ► ATM promotes p53 mRNA-Mdm2 interaction via phosphorylation on Mdm2 S395 ► The p53 mRNA-Mdm2 interaction controls Mdm2 SUMOylation and nuclear trafficking